Non-Sedating Atropisomeric Drugs for Atopic Diseases

描述（由申请人提供）：在我们开发非镇静酮替芬类似物的项目中，我们发现去甲酮替芬（NORK）和N-羟乙基-去甲酮替芬（HENK）具有显著的抗哮喘和抗炎活性，但镇静和抗毒蕈碱活性低于酮替芬。由于阻转异构现象，这些化合物是手性的。因此，我们制备了单独的阻转异构体，并表明S-NONK和S-HENK比外消旋体具有更大的治疗活性，并且R-阻转异构体具有更大的镇静和抗毒蕈碱副作用。在第一阶段，我们评估了候选化合物的阻转异构体的制备方法以及化学和代谢稳定性，以决定是否需要进一步开发这类异构体。此外，我们还比较了生物稳定性，并开始研究阻转异构体的药代动力学特性。我们的结论是，NORK和HENK的阻转异构体在固态下是稳定的，在水溶液中不太稳定，但以温度依赖的方式，和手性稳定的生物环境。对于第二阶段，我们选择去甲酮替芬的S-异构体（“SNORK”）作为“最终先导化合物”，并选择S-羟乙基-去甲酮替芬（SHENK）作为备用化合物。第二期工程的具体目标是：1.改进合成方法，以高化学产率和高对映体过量制备SNORK。2.开发和验证适用于中间体和原料药分析的分析方法。3.使用人微粒体和肝细胞进行SNORK的体外代谢研究，以及相关动物的体内代谢研究。4.准备CA。一公斤GMP级的SNORK，首次在人类研究中使用。5.使用本申请中描述的方法进行其他药理学研究和安全性药理学研究。6.进行IND监管批准所需的毒理学研究。7.撰写SNORK的IND申请，与FDA进行IND前会议，并向FDA提交IND。其目的是将该项目授权给一家在药物开发和监管批准方面具有经验的公司，并有能力在美国和全球范围内将该药物商业化。这项工作的成功完成将提供FDA批准用于临床试验的阻转异构体药物的第一个例子。

DESCRIPTION (provided by applicant): In our program to develop non-sedating ketotifen analogs, we found that norketotifen (NORK) and N-hydroxyethyl-norketotifen (HENK) had significant antiasthmatic and anti-inflammatory activity but less sedation and antimuscarinic activity than ketotifen. These compounds are chiral as a result of atropisomerism. We, therefore, prepared the individual atropisomers, and showed that S-NORK and S-HENK had greater therapeutic activity than the racemates, and that the R-atropisomers had greater sedative and antimuscarinic side effects. In phase I we evaluated the preparation methods, and chemical and metabolic stability of atropisomers of the candidate compounds in order to decide if further development of this class of isomers was warranted. In addition, we have compared the biological stability and began to study pharmacokinetic properties of the atropisomers for the same purpose. We conclude that the atropisomers of NORK and HENK are stable in the solid state, less stable in aqueous solution, but in a temperature-dependent manner, and chirally stable in biological milieus. For phase II we have chosen as "ultimate lead compound" the S-isomer of norketotifen ("SNORK"), and S-hydroxyethyl-norketotifen (SHENK) as a backup compound. The specific aims for this phase II project are: 1. To improve synthetic methods to manufacture SNORK in high chemical yield and in high enantiomeric excess. 2. To develop and validate analytical methods suitable for analysis of intermediates and drug substance. 3. To perform metabolism studies of SNORK in vitro, using human microsomes and hepatocytes, and in vivo, in relevant animals. 4. To prepare ca. one kilogram of GMP-grade SNORK for first in man studies. 5. To perform additional pharmacological studies and safety pharmacological studies, using methodology described in this application. 6. To perform toxicological studies necessary for regulatory approval of an IND. 7. To write an IND application for SNORK, to conduct a pre-IND meeting with the FDA, and to file the IND with the FDA. The aim is to license this project to a company with experience in drug development and regulatory approval, and the ability to commercialize the drug in the U.S. and worldwide. Successful conclusion of this work will afford the first example of an atropisomeric drug approved for clinical trials by the FDA.